NIH begins recruitment for long-term study of diabetes drug efficacy

Newly diagnosed diabetic patients are being recruited for a large national study to compare benefits and risks of four type
2 diabetes drug classes in combination with metformin. More...

Test yourself

MKSAP Quiz: Testing for diabetes

This month's quiz asks readers to evaluate a 48-year-old man with an elevated hemoglobin A1c. More...

From ACP InternistWeekly

Medicare prescribers use twice as many brand-name drugs as VA

Medicare beneficiaries with diabetes take many more brand-name drugs than similar patients treated in the Veterans Affairs
(VA) system, adding as much as $1 billion per year to health care costs, a recent study found. More...

Bariatric surgery in diabetic patients with a body mass index of 30 to 35 kg/m2 is associated with more short-term weight loss and better intermediate outcomes than nonsurgical treatments, but data on long-term
effects are limited, a review found. More...

Intensive insulin therapy (IIT) for inpatient glycemic control can result in more harm than benefit, ACP's Clinical Guidelines
Committee recently reminded clinicians in a best practice advice paper. More...

From ACP Journal Club

In the randomized, controlled Look AHEAD trial, an intensive lifestyle intervention (ILI) was associated with partial remission
of type 2 diabetes when compared with diabetes education and support (DES). More...

Tool of the month

What to do about inexplicably high hemoglobin A1c

When hemoglobin A1c levels are higher than expected, given the self-monitoring blood glucose results, consider several possibilities. More...

FDA update

First drug in new class approved

The FDA recently approved canaglifozin (Invokana) tablets to improve glycemic control in adults with type 2 diabetes, along
with diet and exercise. More...

Keeping tabs

Spotlight on blood pressure control

Intensive blood pressure control may increase diabetic patients' risk of stroke or coronary heart disease, a group of researchers
recently concluded in two separate publications. More...

Highlights

Self-monitoring of blood glucose may improve control

Structured self-monitoring of blood glucose (SMBG) improves control and prompts more medication changes in patients with non-insulin-treated
type 2 diabetes, a study found.

Researchers conducted a 12-month trial with 1,024 Italian patients with a median baseline hemoglobin A1c (HbA1c) of 7.3%,
enrolled between May 2008 and May 2010.

After standardized education, 501 patients were randomized to intensive structured monitoring (ISM group), with fasting, preprandial,
two hours postprandial, and postabsorptive measurements performed three days a week. Another 523 patients were randomized
to active control (AC group), with the same four measurements performed at baseline and at six and 12 months. In the ISM group,
the blood sugar logs were available to be reviewed by the clinicians at the routine clinic visits and thus gave the clinicians
additional data on which to base medication and dietary adjustments. The blood sugar logs were not available to clinicians
caring for the AC group. Results were published online June 4 by Diabetes Care.

Intent-to-treat analysis showed greater HbA1c reductions over 12 months in intensive structured monitoring patients than in
active control patients, (−0.39% vs. −0.27%; between-group difference, −0.12%; 95% CI, −0.210%
to −0.024%; P=0.013). In the per-protocol analysis, intensively monitoring patients also had even greater HbA1c reduction than active control
patients (−0.45% vs. −0.24%; between-group difference, −0.21%; 95% CI, −0.331% to −0.089%; P=0.0007). More intensive patients achieved clinically meaningful reductions in HbA1c (>0.3%) than did active control
patients (P<0.025). Types and doses of diabetes medications were changed more often for intensive patients during visits two, three
and four, but by visit five, the between-group difference did not achieve statistical significance.

Study authors attributed the success in reducing HbA1c in the intensive group to multiple factors. The data may have prompted
clinicians to adjust therapy earlier and more intensely. The intensive group also had a greater decrease in body mass index
(although it was not statistically significant), which may have contributed to improving glycemic control, and this group
may have made more effective lifestyle changes in response to their measurements.

Although both groups reported similar diabetes-specific quality-of-life scores, the study was limited by a number of patients
(200 of 501) who did not complete the intensive self-monitoring as assigned, suggesting that the regimen may have been too
intensive, study authors acknowledged. "It is possible that less frequent use of the glycemic profiles (e.g., a lower number
of weekly profiles) would encourage more patients to use structured SMBG but without sacrificing the beneficial effects seen
in our study," the authors wrote. "Additional studies are needed to further define and elucidate the optimal implementation
of structured SMBG use in these patients."

Researchers studied 120 patients at four teaching hospitals in the U.S. and Taiwan for 12 months, starting in April 2008.
All patients had hemoglobin A1c (HbA1c) levels of 8.0% or higher, body mass index (BMI) between 30 and 39.9, and C peptide
level of more than 1.0 ng/mL and had been in a physician's care for type 2 diabetes for at least six months. All patients
also received lifestyle-medical management, which included medications to control glycemia and cardiovascular disease risk
factors while helping with weight loss.

The lifestyle component included regular counseling on strategies for weight management and increasing physical activity,
as well as self-recording of eating, exercise and weight. Sixty patients were randomized to receive laparoscopic Roux-en-Y
gastric bypass in addition to the lifestyle-medical management. Orlistat and sibutramine were added if needed for the non-gastric
bypass group (until the latter was withdrawn from the market). The main outcome at one year was a triple end point recommended
by the American Diabetes Association: HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic
blood pressure less than 130 mm Hg. Results were published June 5 by the Journal of the American Medical Association.

At 12 months, 28 participants (49%) in the gastric bypass group and 11 (19%) in the lifestyle-medical management group had
reached the composite end point (odds ratio, 4.8). Those in the bypass group needed three fewer medications and lost 26.1%
of their initial body weight compared with 7.9% for the other group. Reaching the composite end point was mostly attributable
to weight loss, according to regression analysis. The largest treatment effect was on diabetes; control of dyslipidemia and
hypertension was similar between the two groups. The numbers of serious adverse events were higher in the bypass group at
22 compared to 15 in the other group. Events in the bypass group included four perioperative complications and six late postoperative
complications; the bypass group also had more nutritional deficiencies.

The merit of gastric bypass surgery for moderately obese patients with type 2 diabetes "depends on whether potential benefits
make risks acceptable," the researchers concluded. An accompanying editorial agreed, adding that "the frequency and severity of complications [reported in the study] is problematic." The editorialists
praised the study for being well designed and more generalizable than past trials. The editorial called for additional research
with greater numbers of patients to determine the perioperative safety of gastric bypass in diabetic patients with BMIs less
than 35 and follow-up beyond one year to help determine long-term safety.

NIH begins recruitment for long-term study of diabetes drug efficacy

Newly diagnosed diabetic patients are being recruited for a large national study to compare benefits and risks of four type
2 diabetes drug classes in combination with metformin.

Beginning recruitment in June, the project is called the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness
(GRADE) Study. The treatments under comparison are sulfonylureas, DPP-4 inhibitors, GLP-1 agonists and long-acting insulin.
The study will compare drugs' effects on glucose levels, adverse events, diabetes complications and quality of life over an
average of nearly five years, according to an NIH press release.

GRADE aims to enroll about 5,000 patients. Investigators at 37 study sites are seeking patients diagnosed with type 2 diabetes
within the last five years. They may be on metformin, but not on any other diabetes medication. During the study, all participants
will take metformin, along with a second medication randomly assigned from among the four classes. Participants will have
their diabetes medications managed free of charge through the study, including at least four medical visits per year, but
will receive other health care through their own clinicians.

Test yourself

MKSAP Quiz: Testing for diabetes

A 48-year-old man is evaluated during a routine examination. He has a 6-year history of hypertension treated with amlodipine
and atenolol and is currently asymptomatic. His father had a myocardial infarction at age 50 years, and his mother developed
type 2 diabetes mellitus at age 64 years.

On physical examination, blood pressure is 138/89 mm Hg, pulse rate is 76/min, and respiration rate is 18/min; BMI is 33.
Central obesity is noted, but all other findings are unremarkable.

Results of laboratory studies show a hemoglobin A1c level of 6.6% and a fasting plasma glucose level of 114 mg/dL (6.3 mmol/L).

From ACP InternistWeekly

Medicare prescribers use twice as many brand-name drugs as VA

Medicare beneficiaries with diabetes take many more brand-name drugs than similar patients treated in the Veterans Affairs
(VA) system, adding as much as $1 billion per year to health care costs, a recent study found.

Researchers conducted a retrospective cohort study using 2008 prescription data on more than 1 million Medicare Part D beneficiaries
with diabetes and more than 500,000 similar veterans. Results were published online June 11 by Annals of Internal Medicine.

In all the studied categories of drugs, Medicare patients were two to three times more likely to be taking a brand-name drug.
Specifically, 35.3% of Medicare patients took brand-name oral hypoglycemics versus 12.7% of veterans. For statins, the rates
were 50.7% of Medicare patients versus 18.2% of VA patients. For angiotensin-converting enzyme inhibitors and angiotensin-receptor
blockers, the rates were 42.5% versus 20.8%, and for insulin analogues, the rates were 75.1% versus 27.0%.

The researchers calculated that reducing brand-name drug usage among these Medicare patients to levels seen in the VA system
would have saved $1.4 billion in 2008. They theorized that the difference may be attributable to the VA's national formulary,
which encourages therapeutic substitution, or the interchange of a generic drug in the same class for a brand-name drug with
no exact generic equivalent (e.g., generic simvastatin for Lipitor). The VA also has a national electronic medical record
with electronic prescribing, limits on pharmaceutical representative visits, and salaried physicians.

Medicare Part D plans, on the other hand, have incentives to allow greater use of brand-name drugs because they compete to
enroll patients. As an example policy difference, only about 10% of studied Part D patients faced step therapy requirements
to take atorvastatin or valsartan, while the VA requires step therapy and prior authorization for both those drugs. Even the
VA, however, showed substantial geographic variation in brand-name drug use, which the study authors attributed to local adjudication
of prior authorizations and local physician practice patterns.

The VA scores as well as or better than Medicare on quality measures for diabetes care, the authors noted, and the system's
lower rates of brand-name usage should be attainable by Medicare. "These potential savings could be realized through policies
that promote Part D plan efficiency and by encouraging physicians to consider costs and value in their prescribing," they
concluded.

Bariatric surgery in diabetic patients with a body mass index of 30 to 35 kg/m2 is associated with more short-term weight loss and better intermediate outcomes than nonsurgical treatments, but data on long-term
effects are limited, a review found.

Researchers reviewed 32 surgical studies and 11 systematic reviews on nonsurgical treatments, as well as 11 large nonsurgical
studies published after those reviews, for data on weight loss, metabolic outcomes and adverse events. Results appeared in the June 5 Journal of the American Medical Association.

In three randomized clinical trials totaling 290 subjects, surgery was associated with greater weight loss (range, 14.4 to
24 kg) and glycemic control (range, 0.9 to 1.43 point improvements in hemoglobin A1c levels) during one to two years of follow-up
compared to nonsurgical treatment. Indirect comparisons of evidence from observational studies of about 600 bariatric procedures
and meta-analyses of more than 300 randomized, controlled trials of nonsurgical therapies support this finding as far out
as two years of follow-up.

However, the authors wrote, there are no robust surgical data beyond five years of follow-up on outcomes such as glucose control
and macrovascular and microvascular outcomes. Randomized controlled trial data on nonsurgical therapies show benefits at 10
years of follow-up or more.

In 14 studies reviewed for patient safety, surgeon-reported adverse events were low, but data were from select centers and
surgeons. Only one death was reported in a patient receiving gastric banding with complications of a gastric perforation.
Cardiovascular, respiratory, gastrointestinal and metabolic adverse events were relatively rare. Other complications included
infections or seroma, incisional hernias, stricture, anastomotic leaks, and ulcers. Several complications specific to gastric
banding were reported: band slippage in 3% of 361 patients, port or tube problems in about 1.9% of 462 patients, band removal
in 3.3% of 210 patients and pouch dilation in 5.4% of 240 patients.

Researchers noted that these studies may represent best-case outcomes, since they were often small-population and single-site
reports without long-term follow up.

"In contrast, behavior and medication interventions have been studied extensively in a wide variety of clinical settings;
several large, long-term randomized clinical trials have found improved [hemoglobin]A1c levels for up to 10 years," researchers
wrote. "Therefore, the evidence for longer-term control of glucose in patients with diabetes is stronger for behavioral and
medication therapies than for surgery."

Intensive insulin therapy (IIT) for inpatient glycemic control can result in more harm than benefit, ACP's Clinical Guidelines
Committee recently reminded clinicians in a best practice advice paper.

ACP recommends that clinicians should target a blood glucose level of 140 to 200 mg/dL if IIT is used in surgical or medical
intensive care unit patients, and clinicians should avoid targets less than 140 mg/dL because harms are likely to increase
with lower blood glucose targets, noted the paper, published in the American Journal of Medical Quality on May 23.

In a review of the evidence, ACP's Clinical Guidelines Committee found that IIT with a goal of achieving normal or near-normal
blood glucose in patients with or without diabetes does not provide substantial benefits and may lead to harm. IIT costs include
implementation in a hospital and downstream expenses incurred to manage the consequent harms. No recent cost-effectiveness
studies have incorporated results from recent trials to evaluate the impact of IIT.

"Even in light of the new evidence, many systems continue to recommend moderate blood glucose control because of the association
of high blood glucose with infection, poor wound healing, dehydration, and other complications. Clinicians caring for these
patients must keep the harms of hypoglycemia in mind when managing hyperglycemia and should avoid aggressive glucose management,"
the ACP experts wrote.

From ACP Journal Club

In the randomized, controlled Look AHEAD trial, an intensive lifestyle intervention (ILI) was associated with partial remission
of type 2 diabetes when compared with diabetes education and support (DES).

The study was published in the Dec. 19, 2012, Journal of the American Medical Association. A summary of the study was published in the January ACP DiabetesMonthly. The following commentary by Ma P. Kyithar, MD, and Sean F. Dinneen, MD, FACP, was published in the ACP Journal Club section of the May 21 Annals of Internal Medicine.

The large Look AHEAD trial asked a question of major importance to patients, health care practitioners, and policymakers:
Does ILI reduce the incidence of cardiovascular events among obese patients with type 2 diabetes? Look AHEAD found that, compared
with DES, ILI did not reduce cardiovascular events. Gregg and colleagues report the results of secondary analyses, some expected
(e.g., diabetes remission is more likely among persons with relatively short-duration, compared with longer-duration, type
2 diabetes) and some surprising (e.g., a mean reduction in body weight of almost 9% in year 1 in the ILI group was associated
with a complete remission rate of only 1.3%).

Our understanding of the determinants of remission of type 2 diabetes is incomplete, as is our understanding of prevention
of type 2 diabetes among persons at risk. An interesting analogy can be drawn between duration of remission (for many Look
AHEAD patients the phenomenon was transient) and the controversy around whether lifestyle interventions really prevent, or
simply delay, onset of type 2 diabetes. Why does bariatric surgery seem to have a different trajectory of benefit in terms
of diabetes remission? What are the relative contributions of improvement in β-cell function, improvement in insulin
action, and reduction in liver fat to the effect of ILI on remission? Answering these questions requires further research.
In the meantime, the low rate of complete remission and the lack of a statistically significant effect of ILI on major cardiovascular
events in Look AHEAD is a setback to the proponents of lifestyle modification (before metformin) in the care pathway for management
of type 2 diabetes.

FDA update

First drug in new class approved

The FDA recently approved canaglifozin (Invokana) tablets to improve glycemic control in adults with type 2 diabetes, along
with diet and exercise.

The drug is the first sodium-glucose co-transporter 2 (SGLT2) inhibitor to be approved. Safety and effectiveness were evaluated
in nine clinical trials of over 10,000 patients, which showed improvements in hemoglobin A1c and fasting plasma glucose. The
drug has been studied as a stand-alone therapy and in combination with metformin, sulfonylureas, pioglitazone and insulin.
It should not be used in patients with type 1 diabetes, diabetic ketoacidosis, severe renal impairment or end-stage renal
disease. The most common side effects were vulvovaginal candidiasis and urinary tract infection. Because the drug is associated
with a diuretic effect, it can cause a reduction in intravascular volume leading to orthostatic or postural hypotension.

The FDA is requiring five postmarketing studies: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to
monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver
abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies.

Keeping tabs

Spotlight on blood pressure control

Intensive blood pressure control may increase diabetic patients' risk of stroke or coronary heart disease, a group of researchers
recently concluded in two separate publications.

Both findings were based on a prospective cohort study of 17,536 black and 12,618 white patients with diabetes (many low-income)
treated in the Louisiana State University Hospital System. Patients had their blood pressure measured upon entering the study
and occasionally during follow-up, which lasted for a mean of about six years. For both stroke and new diagnosis of coronary
heart disease (CHD) and for both black and white patients, the study found a U-shaped association—a higher risk of
disease associated with both low and high blood pressure.

In the first analysis, published by Diabetes Care on May 20, the hazard ratios for CHD (with a reference group of 130-139/80-90 mm Hg) for black patients were 1.73 for blood
pressure below 110/65 mm Hg, 1.16 for blood pressure of 110-119/65-69 mm Hg, 1.04 for blood pressure of 120-129/70-80 mm Hg,
1.06 for blood pressure of 140-159/90-100 mm Hg, and 1.11 for a blood pressure of 160/100 mm Hg or higher. The respective
hazard ratios for white patients were 1.60, 1.27, 1.08, 0.95 and 0.99. This U-shaped association was present in all younger
patients but changed to an inverse association in patients 60 and over.

In the stroke analysis, published by the Journal of Clinical Endocrinology and Metabolism on May 28, the reference group was 120-129/70-80 mm Hg and hazard ratios for stroke in black patients were 1.88 for blood
pressure less than 110/65 mm Hg, 1.05 for a blood pressure of 110-119/65-69 mm Hg, 1.05 for a blood pressure of 130-139/80-90
mm Hg, 1.12 for a blood pressure of 140-159/90-100 mm Hg, and 1.47 for a blood pressure of 160/100 mm Hg or higher. The respective
hazard ratios for white patients were 1.42, 1.22, 0.88, 1.02 and 1.28.

The researchers could not determine the cause of these U-shaped associations, but they concluded that intensive blood pressure
control may increase risk for CHD and stroke. For CHD prevention in diabetic patients, "it might be advisable to maintain
blood pressure between 130-139 and 80-89 mmHg and to recommend less intense goals to elderly patients than to younger ones,"
they wrote. In the stroke study, they concluded that a blood pressure target of less than 130/80 mm Hg "may provide cerebrovascular
protection," although they added that for patients at high risk of a cerebrovascular event, maintaining blood pressure in
the range of 120-129/70-79 mm Hg may be appropriate.

MKSAP Answer and Critique

The correct answer is C. Repeat measurement of hemoglobin A1c value. This item is available to MKSAP 16 subscribers as item
24 in the Endocrinology section. Information about MKSAP 16 is available online.

This patient is at high risk for diabetes mellitus and should have his hemoglobin A1c value remeasured. He has a family history
of type 2 diabetes and coronary artery disease, is obese, and has hypertension. According to the American Diabetes Association,
in the absence of unequivocal symptomatic hyperglycemia, the diagnosis of diabetes must be confirmed on a subsequent day by
repeating the same test suggestive of diabetes (in this patient, the hemoglobin A1c measurement). If results of two different
diagnostic tests are available and both are diagnostic for diabetes, additional testing is not needed. Although this patient's
hemoglobin A1c value is diagnostic of diabetes, his fasting serum glucose level is only in the range of impaired fasting glucose.
Because this patient had two different tests with discordant results, the test that is diagnostic of diabetes (the hemoglobin
A1c measurement) should be repeated to confirm the diagnosis.

In this patient without any hyperglycemic symptoms, remeasuring his hemoglobin A1c level is a much simpler and less burdensome
way of confirming the diagnosis of diabetes than performing an oral glucose tolerance test.

Because results of measurement of the hemoglobin A1c value and fasting plasma glucose level were discordant, not performing
any additional testing is inappropriate.

Key Point

If results of two different diagnostic tests for diabetes mellitus are discordant, the test that is diagnostic of diabetes
should be repeated.

Test yourself

A 66-year-old man is evaluated for a persistent rash for 6 years' duration. The rash waxes and wanes in severity, and it becomes pruritic only after he becomes hot and sweating, such as when he mows the lawn or exercises. It has always been limited to his back and lower chest. He has never treated it. The patient is otherwise well, has no other medical problems, and takes no medication. Following a physical exam, what is the most likely diagnosis?

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